High-density lipoprotein (HDL) is the largest of the five major groups of lipoproteins. Other lipoproteins include chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL). HDL and other lipoproteins enable cholesterol and other lipids (e.g., triglycerides) to be transported within the bloodstream, despite their hydrophobic nature. About thirty percent of blood cholesterol is carried by HDL in healthy adults.
ATP-binding cassette transporter A1 (ABCA1) is an integral cell membrane protein that exports excess cholesterol from cells in conjunction with phospholipid that is necessary for the initial lipidation of ApoA1 to form nascent high density lipoprotein cholesterol (HDL-c). ABCA1 deficiency leads to very low plasma levels of HDL-c. In contrast, ABCA1 overexpression reportedly protected C57B1/6 mice from diet-induced atherosclerosis. Increasing ABCA1 transcription by enhancing its regulatory gene control by liver X factor (LXR) has led to the induction of not only HDL biogenesis, but also to an adverse increase in lipogenesis, leading to undesirable hepatic steatosis.
HDL-c is formed in the liver and the intestines by the lipidation of apolipoprotein A1 (apoA1) mediated by the ABCA1 transporter protein. Numerous studies of cultured cells, human HDL deficiencies, and animal models have shown that ABCA1 is a major determinant of plasma HDL levels and a potent atheroprotective factor. The role of ABCA1 in the liver for the formation of plasma HDL is well established, but it has been unclear whether stimulation of ABCA1 production will enhance lipidation and secretion of nascent HDL thereby resulting in an increase in plasma HDL-c levels.
The metabolism of HDL is complex and several factors contribute to the transport of cholesterol from arteries to the liver for excretion or re-use (reverse cholesterol transport). Some key players in reverse cholesterol transport include ABCA1, ABCG1, apoA1, apoE, LXR, Niemann Pick proteins 1 and 2 (NPC1 and NPC2) sterol regulating element binding protein (SREBP), CD36, acyl cholesterol acyl transferase (ACAT) and scavenger receptor A1 (SRA1). Many of these proteins have been considered as drug targets for enhancing blood HDL-c levels; however, the effects of targeting, enhancing the activity of, or otherwise interfering with the normal activity and expression of any of these individual proteins is unpredictable. High cholesterol also commonly is treated by inhibiting production of cholesterol in the liver (e.g., by inhibiting HMG-CoA reductase) or by inhibiting digestion of fats (e.g., by inhibiting bile acid production).
Plasma HDL-c and LDL-c levels are routinely measured as indicators of systemic atherosclerosis resulting in arterial blockage. HDL can remove cholesterol from within arteries and transport the cholesterol back to the liver for excretion or re-utilization. Individuals with higher levels of HDL-c have a reduced tendency for cardiovascular diseases. Low HDL-c cholesterol levels (less than about 40 mg/dL or about 1 mmol/L) are associated with increased risk of heart disease. In patients with Tangier disease (also known as “familial alpha-lipoprotein deficiency”), a rare inherited disorder, mutations in chromosome 9q31 lead to an inactive form of ABCA1. The inactive ABCA1 leads to severely depressed levels of HDL in the blood. Currently, there is no effective treatment for Tangier disease.
Because of the positive epidemiological correlation between HDL-c levels in the blood and reduced risk of heart disease, as well as the link between HDL and Tangier disease, there is an ongoing need for new methods of increasing blood HDL-c levels. The present application addresses this ongoing need.